Process for production of a betaine such as carnitine

Abstract

According to the present invention, by using 4-halogeno-3-hydroxybutanamide as a substrate in quaternary amination reaction with trialkylamine which is an important step in betaine (such as carnitine) preparation processes, it becomes possible to reduce the production of crotonic acid derivatives (the major by-product) greatly compared to conventional processes. Consequently, it becomes possible to prepare a betaine, such as carnitine, at a high yield.

1. A process for preparing a 4-trialkylamino-3-hydroxybutyramide halide represented by formula (2′) below: 
       
         
           
           
               
               
           
         
         wherein A 1 , A 2  and A 3  are independent from each other, may be the same or different, and individually represent a C 1 -C 20  hydrocarbon group which may have a substituent(s), and X 1  is a halogen atom; said process comprising a step of quaternary aminating 4-halogeno-3-hydroxybutyramide represented by formula (2) below: 
       
       
         
           
           
               
               
           
         
         wherein X 1  is a halogen atom; with a trialkylamine represented by (NA 1 A 2 A 3 ). 
       
     
     
       2. The process according to claim wherein said trialkylamine is trimethylamine. 
     
     
       3. A process for preparing a betaine represented by formula (1) below or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein A 1 , A 2  and A 3  are independent from each other, may be the same or different, and individually represent a C 1 -C 20  hydrocarbon group which may have a substituent(s); 
         said process comprising a step of hydrolyzing a halogenated 4-trialkylamino-3-hydroxybutanamide represented by formula (2′) below obtained by the method according to  claim 1 : 
       
       
         
           
           
               
               
           
         
         wherein A 1 , A 2  and A 3  are independent from each other, may be the same or different, and individually represent a C 1 -C 20  hydrocarbon group which may have a substituent(s), and X 1  is a halogen atom. 
       
     
     
       4. The process according to  claim 3 , wherein A 1 , A 2  and A 3  individually represent a methyl group. 
     
     
       5. The process according to  claim 1 , wherein said 4-halogen-3-hydroxybutyramide represented by formula (2) below: 
       
         
           
           
               
               
           
         
         wherein X 1  is a halogen atom; 
         is obtained by a step of amidating 4-halo-3-hydroxybutyronitrile represented by formula (3) below: 
       
       
         
           
           
               
               
           
         
         wherein X 1  is a halogen atom. 
       
     
     
       6. The process according to  claim 5 , wherein the amidation is performed with a nitrilehydratase. 
     
     
       7. The process according to  claim 6 , wherein the nitrilehydratase is produced by a microorganism selected from the group consisting of microorganisms belonging to the genuses  Achromobacter, Acidovorax, Agrobacterium, Arthrobacter, Bacillus, Brevibacterium, Burkholderia, Candida, Caseobacter, Comamonas, Corynebacterium, Dietzia, Enterobacter, Erwinia, Geobacillus, Gordona, Klebsiela, Microascus, Morganella, Pantoea, Proteus, Pseudomonas, Pseudonocardia, Rhodococcus, Rhizobium, Serratia, Streptomyces, Syctalidium  and  Tukamurella.    
     
     
       8. The process according to  claim 5 , wherein the step of preparing said 4-halogeno-3-hydroxybutyramide is performed at temperatures within a range from a temperature at which the reaction solution does not freeze to about 5° C. 
     
     
       9. The process according to  claim 5 , wherein said 4-halo-3-hydroxybutyronitrile represented by formula (3) below: 
       
         
           
           
               
               
           
         
         wherein X 1  is a halogen atom; 
         is obtained by a step of reacting an epihalohydrin represented by formula (4) below: 
       
       
         
           
           
               
               
           
         
         wherein X 1  is a halogen atom; 
         or 1,3-dihalo-2-propanol represented by formula (5) below: 
       
       
         
           
           
               
               
           
         
         wherein X 1  is as defined above; 
         and X 2  is independent from X 1  and represents an identical or different halogen atom; 
         with hydrogen cyanide or a cyanide salt. 
       
     
     
       10. The process according to  claim 9 , wherein the reaction with hydrogen cyanide or a cyanide salt is performed in the presence of an enzyme catalyst. 
     
     
       11. The process according to  claim 10 , Wherein said enzyme catalyst is a halohydrin epoxidase. 
     
     
       12. The process according to  claim 11 , wherein said 4-halo-3-hydroxybutyronitrile represented by formula (3) below: 
       
         
           
           
               
               
           
         
         wherein X 1  is a halogen atom; 
         is produced in an (R)-isomer excessive manner. 
       
     
     
       13. The process according to  claim 11 , wherein said halohydrin epoxidase is produced by a microorganism selected from the group consisting of microorganisms belonging to the genuses  Corynebacterium, Microbacterium, Agrobacterium, Mycobacterium  and  Arthrobacter.